Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:24](=[O:26])[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:27])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), piperazine-1-carboxylic acid tert-butyl ester (31 mg, 2 eq.), and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (20 mg).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[CH:21]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(CCOCCO)cc2Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(CCOCCO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2-hydroxyethoxy)ethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (31 mg, 0.048 mmol) in THF:MeOH:H2O (2:3:1, 0.6 mL) was added LiOH—H2O (2.8 mg, 0.067 mmol). After being stirred overnight at room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed 1× with brine, 1× with brine containing 1% NaHSO4 and 1× with brine prior to drying over Na2SO4. Concentration gave 22 mg of title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.38 (s, 1H), 7.27 (s, 1H), 7.07 (s, 4H), 4.47 (dd, J=9.6, 3.0 Hz, 1H), 4.02 (s, 2H), 3.85 (d, J=12.3 Hz, 1H), 3.71-3.62 (m, 5H), 3.53-3.46 (m, 4H), 3.39-3.37 (m, 2H), 3.13-3.03 (m, 1H), 2.97-2.87 (m, 1H), 2.58 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H); MS ESI (m/z) 481 (M+1)+, calc. 480.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[Cl:13][C:14]1[C:15]([CH3:31])=[C:16]2[C:20](=[C:21]([CH3:28])[C:22]=1[CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH2:19][C:18]([CH3:30])([CH3:29])[CH2:17]2.[CH3:32]O>>[Cl:13][C:14]1[C:22]([CH:23]2[CH2:3][C:4](=[O:5])[CH2:26][C:25](=[O:27])[CH2:24]2)=[C:21]([CH3:28])[C:20]([CH3:19])=[C:16]2[C:15]=1[CH2:31][C:18]([CH2:30][CH3:32])([CH3:29])[CH2:17]2
Reactant: CO
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c2c(c(C)c1Cl)CC(C)(C)C2
Agent: [Na]
Product: CCC1(C)Cc2c(C)c(C)c(C3CC(=O)CC(=O)C3)c(Cl)c2C1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1.53 g of sodium in 100 ml of absolute methanol was added 10 ml of diethyl malonate, and then the reaction mixture was added 12.65 g of 4-(5-chloro-2,2,4,7-tetramethylindan-6-yl)-3-buten-2-one in 50 ml of absolute methanol. After refluxing for 4 hours, the reaction mixture was evaporated under reduced pressure and then added 70 g of 10% aqueous solution of NaOH. After refluxing for 4 hours, the reaction mixture was cooled to room temperature and washed twice with diethyl ether. Concentrated hydrochloric acid was added dropwise into the boiling aqueous layers until the bubble of gas ceased and then the reaction mixture was cooled to room temperature. Solid produce was collected and dried to afford 11.9 g of the titile compound as yellow solid.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=O.Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC>[NH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)C(=O)Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A stirred solution of 0.35 g (1.07 mmol) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K2CO3. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg (92%) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. 1H NMR (300 MHz CDCl3) δ 7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C8H4NOClF4(M+): 240.9918, found: 240.9914. 19F NMR (282 MHz, CDCl3) δ −132.7(s, 1F), −70.6(s, 3F).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][C:22]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1)=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
(S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.3 g, 1 mmol), acetic anhydride (0.12 g, 1.2 mmol) and triethylamine (0.5 g, 5 mmol) were added to 10 mL ethyl acetate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to yield the crude product. The crude product was recrystallized with ethyl acetate to provide 0.30 g of linezolid in 88% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][C:29]1([CH3:42])[CH3:41])=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:32][CH2:33][NH:28][C:29]([CH3:42])([CH3:41])[CH2:30]4)=[CH:35][N:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n1C1CCCC1
Yield: 28.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.17 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.15 mmol) gave 7-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 25%). MS (ESI) m/z 463.3 (M+H)+
Reaction SMILES: O.C(O[C:7](=[O:10])[CH:8]=[O:9])CCC.[CH3:11][NH:12][C:13]([NH2:15])=[O:14]>C(O)(=O)C>[OH:10][CH:7]1[N:12]([CH3:11])[C:13](=[O:14])[NH:15][C:8]1=[O:9]
Reactant: CCCCOC(=O)C=O
Reactant: CNC(N)=O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)NC(=O)C1O
Yield: 80 %

Procedure:
15.0 g of glyoxylic acid n-butyl ester monohydrate and 7.4 g of N-methylurea were refluxed in an 80% aqueous solution of acetic acid for 1 hour. After the solvent was removed by distillation, a small amount of methanol was added to the residue and the insoluble matter was filtered off. The filtrate was then evaporated to dryness under reduced pressure. The resulting crude crystals were recrystallized from ethyl acetate to give 10.4 g of 5-hydroxy-1-methylhydantoin (compound 1) in the form of white crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:7])[CH2:5][NH2:6].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O.[B-][C:17]#[N:18].[Na+]>CO>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:2]([CH2:12][C:11]1[CH:10]=[CH:9][CH:14]=[CH:17][N:18]=1)[CH2:3][CH:4]([OH:7])[CH2:5][NH:6][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1
Reactant: NCC(O)CN
Reactant: O=Cc1ccccn1
Reactant: [B-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: OC(CNCc1ccccn1)CN(Cc1ccccn1)Cc1ccccn1
Reaction time: 72 h
Yield: 25746.7 %

Procedure:
After concentrated hydrochloric acid (60 mL) was added to a solution of 1,3-diaminopropan-2-ol (32.6 g, 362 mmol) in methanol (2400 mL) and further 2-pyridine aldehyde (116.3 g, 1.09 mmol) was added dropwise, sodium cyanotrihydroborate (50.16 g, 798 mmol) was added. After the completion of the addition, reaction was carried out at room temperature for 3 days. After concentrated hydrochloric acid was added to the reaction solution to adjust pH to 6, the solution was concentrated to a proper extent and a 0.1 N aqueous sodium hydroxide solution was added to adjust pH to 7 and the solution was extracted using chloroform. The obtained chloroform phases were collected and dried and thereafter concentrated. The obtained residue was refined by silica gel column chromatography to obtain 34 g of an aimed product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](CN)=[C:4]([N+:11]([O-])=O)[CH:3]=1.O.[NH3:15].[ClH:16].[C:17](O)(=O)C>CCOCC.[Zn].C(OCC)(=O)C>[Cl:16][C:6]1[CH:5]=[C:4]([NH2:11])[C:3]([NH:15][CH3:17])=[CH:2][C:7]=1[Cl:8].[ClH:1]
Reactant: CC(=O)O
Reactant: NCc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: N
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CNc1cc(Cl)c(Cl)cc1N
Temperature: 20 °C

Procedure:
A solution of (4,5-dichloro-2-nitrophenyl)methylamine (500 mg) in acetic acid (7.5 ml) is treated portionwise with zinc powder (740 mg). The reaction medium is stirred at ambient temperature (20° C.) until complete reduction. Water (13 ml) and 28% ammonia are added to pH 7, and then the reaction medium is depleted using ethyl acetate (3×50). The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is taken up in ether (50 ml) and then 2N HCl is added thereto. The solid formed is filtered off. 4,5-Dichloro-N-methylbenzene-1,2-diamine is isolated in its hydrochloride form (510 mg), and is used in the next state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19].Cl>C(=S)=S>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:18](=[O:20])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 200 g of 2-fluorobiphenyl in 1500 ml of carbon disulfide was cooled to 0°-5°C and successively treated with 200 g of aluminum chloride over a period of 140 minutes and 113 g of acetyl chloride over a period of 165 minutes. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture then was poured carefully into a mixture of ice and aqueous hydrochloric acid. Organic materials were extracted from the resulting acidic mixture with a mixture of diethyl ether and ethyl acetate. The organic extract was washed successively with water, ten percent aqueous sodium hydroxide, and water, and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure and the solid residue was recrystallized from hexane to give 4'-(2-fluorophenyl)acetophenone. Recrystallization of the material from hexane gave two crops of crystals having the following elemental analyses:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH:38]=[C:37]([CH3:47])[C:33]=1[C:34](O)=[O:35]>>[CH3:47][C:37]1[CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH:40]=[C:32]([CH3:31])[C:33]=1[C:34]([NH:19][CH2:18][CH2:17][CH:16]([N:13]1[CH2:12][CH2:11][CH:10]([CH:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)[CH2:15][CH2:14]1)[CH3:20])=[O:35]
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Reactant: Cc1cccc(OC(c2ccc(C(F)(F)F)cc2)C2CCN(C(C)CCN)CC2)n1
Product: Cc1cccc(OC(c2ccc(C(F)(F)F)cc2)C2CCN(C(C)CCNC(=O)c3c(C)cc(-c4ccncc4)cc3C)CC2)n1
Yield: 47.6 %

Procedure:
Using general procedure E, 3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (see EXAMPLE 23) (40 mg, 0.10 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (24 mg, 0.11 mmol) afforded COMPOUND 50 (30 mg, 50%). 1H NMR (CDCl3) δ 0.50-1.10 (m, 2H), 0.95, 0.96 (d, 3H, J=6.1 Hz), 1.47-2.06 (m, 5H), 2.20, 2.22 (s, 3H), 2.26-2.45 (m, 1H), 2.42 (s, 6H), 2.56-2.87 (m, 4H), 3.24-3.41 (m, 1H), 3.76-3.94 (m, 1H), 5.16, 5.23 (d, 1H, J=8.1 Hz), 6.29 (dd, 1H, J=8.4, 4.5 Hz), 6.57 (dd, 1H, J=7.5, 2.7 Hz), 7.18-7.24 (m, 3H), 7.36-7.40 (m, 4H), 7.50 (d, 2H, J=4.8 Hz), 8.35, 8.47 (br s, 1H), 8.61-8.64 (m, 2H). 13C NMR (CDCl3) δ 13.17, 13.39, 19.42, 23.99, 24.03, 28.26, 28.90, 29.08, 29.87, 30.78, 31.32, 39.58, 39.69, 42.28, 44.06, 44.16, 51.95, 52.10, 60.03, 60.38, 79.67, 79.83, 106.97, 107.01, 116.03, 121.47, 124.06 (q, J=272 Hz), 124.88, 124.92, 125.93, 127.35, 129.43 (q, J=32 Hz), 135.25, 137.90, 137.97, 138.77, 139.38, 144.73, 147.70, 150.32, 156.19, 162.20, 169.26, 169.54. ES-MS m/z 631 (M+H). Anal. Calcd. for C37H41F3N4O2: C, 70.06; H, 6.58; N, 8.83; F, 8.98. Found. C, 70.15; H, 6.50; N, 8.79; F, 8.78.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.C(#N)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[NH:20]([CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: O
Solvent: CC#N
Product: CC1CCC(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.11 %

Procedure:
148.7 g. (0.50 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 250 ml. of acetonitrile and 100 ml. of aniline are further added. The solution is stirred for 2 days in a nitrogen gas atmosphere at room temperature. 1000 ml. of water is added and the mixture is stirred for a further half an hour. The crystals are filtered and washed with water and finally reboiled in 1400 ml. of methanol. 128.8 g. (86.11%) of 9-anilino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained. Melting point: 198°-199° C.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(NC2CCCCC2)[CH2:35]CCC[CH2:31]1.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:24]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:35][CH2:30][CH2:31][C@H:19]3[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:18]([NH2:24])[C:19](C#N)=[CH:20][CH:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.[CH:29]([NH2:31])=[NH:30]>CCCCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:18]3[C:19]([C:29]([NH2:31])=[N:30][CH:25]=[N:24]3)=[CH:20][CH:21]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc([C@@H]2CCCN(C(=O)OCc3ccccc3)C2)n1N
Reactant: N=CN
Solvent: CCCCO
Product: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
The product from step 5 (3.57 g, 11.00 mmol) was dissolved in 40 mL of n-BuOH and treated with formamidine acetate (11.48 g, 110.0 mmol). The mixture was heated to reflux for 8 h whereupon an additional 2.75 g (26.4 mmol) of formamidine acetate was added. Heating continued for 1.5 h and then the reaction was allowed to cool to rt overnight. The black reaction mixture was filtered through Celite® and the Celite® pad was washed with 100 mL of EtOH. The filtrate was concentrated in vacuo and the residue was partitioned between water (100 mL) and 3×75 mL of EtOAc. The combined organic extracts were washed with water, 2M aq. Na2CO3, brine, dried over Na2SO4 and filtered through a 1″ (d) by 4″ (w) pad of SiO2 (pre-wetted with EtOAc) and the pad was washed with ˜500 mL of EtOAc. The filtrate was concentrated in vacuo and the residue dried in a vacuum oven at 40° C. for 2 h to give the title compound as a yellowish brown solid (3.60 g). 1H NMR (300 MHz, CD3OD) δ 7.82 (s, 1H), 7.64 (bs, 2H), 7.42-7.24 (m, 5H), 6.81 (d, 1H), 6.44 (d, 1H), 5.08 (bs, 2H), 4.2 (d, 1H), 3.96 (d, 1H), 3.23 (m, 1H), 3.16-2.84 (m, 2H), 2.03, (m, 1H), 1.79-1.62 (m, 2H), 1.46 (m, 1H). ES-MS m/z 352.2 [M+H]+, HPLC RT (min) 2.49.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[C:8](=O)([O-])[O-:9].[K+].[K+].C(N(CC)CC)C.Br[C:22]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[C:30]2[C:23]=1[CH2:24][CH:25]1[CH2:29][O:28][N:27]=[C:26]12.[C]=O>O1CCOCC1>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([C:22]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[C:30]2[C:23]=1[CH2:24][CH:25]1[CH2:29][O:28][N:27]=[C:26]12)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cn1nccc1O
Reactant: CS(=O)(=O)c1ccc(Br)c2c1C1=NOCC1C2
Agent: [C]=O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c3c2CC2CON=C32)c1O
Temperature: 1300 °C
Reaction time: 0.08 h

Procedure:
0.62 g (6.33 mmol) of 5-hydroxy-1-methylpyrazole, 1.75 g (12.66 mmol) of dry potassium carbonate, 1.28 g (12.67 mmol) of triethylamine and 0.22 g (0.30 mmol) of bis-(triphenylphosphane)palladium dichloride were added to a suspension of 2.0 g (6.33 mmol) of 5-bromo-8-methylsulfonyl-3a,4-dihydro-3H-indeno[1,2-c]-isoxazole in 100 ml of dioxane. In a miniautoclave, a carbon monoxide pressure of 20 bar was applied, the mixture was stirred for 5 minutes and the autoclave was vented. This procedure was repeated 3 times. The autoclave was subsequently heated to 1300° C., a carbon monoxide pressure of 20 bar was applied once more and the mixture was stirred for 24 hours. After cooling and venting, the solvent was removed, and the residue was taken up in water, adjusted to pH 11 and washed with methylene chloride. The mixture was subsequently acidified to pH 4 using 10 percent strength hydrochloric acid and extracted with methylene chloride. The combined organic phases were washed with saturated ammonium chloride solution and dried, and the solvent was removed. This gave 0.58 g (25%) of (5-hydroxy-1-methyl-1H-pyrazol-4-yl)-(8-methylsulfonyl-3a,4-dihydro-3H-indeno[1,2-c]isoxazole)-methanone in the form of a dark oil.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][C:2]1=[O:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[K])(C)(C)C.O.CCOC(C)=O>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:11])[N:1]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 0 °C

Procedure:
Ethyl (S)-(+)-2-pyrrolidone-5-carboxylate (1 g, 6.36 mmol) and benzyl bromide (0.76 mL, 6.36 mmol) were placed in dry THF (30 mL). The reaction mixture was stirred and cooled to 0° C. A 1M solultion of tert-BuOK was added dropwise (6.36 mL, 6.36 mmol) and the reaction was stirred for an additional 0.5 h at 0° C. and allowed to come to room temperate where it was stirred for 24 hours under N2. The reaction was then dissolved into a 1:1 mixture of H2O/EtOAc. The organic layer was washed with 1M HCl, H2O and brine, and then dried over MgSO4 to afford N-benzyl-L-pyroglutamic acid ethyl ester an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.C[NH:27]C1C=CC=CC=1>>[NH2:27][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: CNc1ccccc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 13 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-methylaniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 303.38; found mol. wt. (M+H) 304.2
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[N:4][CH:3]=1.[NH3:19]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[N:4][CH:3]=1
Reactant: N
Reactant: CCCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Solvent: CO
Product: CCCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 5-bromo-2-(3-propylureido)isonicotinate (Intermediate 42, 128 g, 405 mmol) and 7N ammonia in methanol (1 L) was allowed to stir at room temperature for 3 d. Stirring for the reaction was then stopped and the solids were allowed to settle. The precipitated was then vacuum filtered, rinsed with methanol (2×500 mL), and then dried on the high vacuum pump overnight, yielding 123 g (quant) of 5-bromo-2-(3-propylureido)isonicotinamide as a white solid.